<br>驱动蛋白轻链 1 稳定胰岛素受体底物 1，在成肌细胞分化过程中调节 IGF-1-AKT 信号通路,The FASEB Journal

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驱动蛋白轻链 1 稳定胰岛素受体底物 1，在成肌细胞分化过程中调节 IGF-1-AKT 信号通路
The FASEB Journal ( IF 4.4 ) Pub Date : 2024-02-01 , DOI: 10.1096/fj.202201065rr
Zihao Qu ₁ , Linjing Shi ₁ , Zhen Wu ₂ , Peng Lin ₁ , Guangan Zhang ₃ , Xiaoxia Cong ₃ , Xiang Zhao ₁ , Huiqing Ge ₄ , Shigui Yan ₁ , Liangjun Jiang ₁ , Haobo Wu ₁

Affiliation

IGF 信号通路在调节骨骼肌生成中起着至关重要的作用。我们已经证明，kinesin-1 马达的重链 KIF5B 通过调节 IGF-p38MAPK 激活来促进成肌细胞分化。然而，驱动蛋白轻链 (Klc) 在 IGF 途径和成肌细胞分化中的作用仍然难以捉摸。在这项研究中，我们发现 Klc1 在肌肉再生过程中上调，而在衰老小鼠肌肉和 mdx（X 连锁肌营养不良症）小鼠的营养不良肌肉中下调。功能获得和功能丧失实验进一步表明，Klc1 促进 AKT-mTOR 活性并正向调节肌原性分化。我们进一步发现 IRS1（IGF-1 信号转导的关键节点）的表达水平在 Klc1 耗尽的成肌细胞中下调。免疫共沉淀研究表明，IRS1 通过其 PTB 结构域与 Klc1 的 88-154 个氨基酸序列相互作用。值得注意的是，在小鼠和人类的衰老和骨质疏松骨骼肌样本中发现 Klc1 水平降低。综上所述，我们的研究结果表明，Klc1 通过稳定 IRS1 在肌生成过程中 IGF-AKT 通路的调节中发挥着至关重要的作用，这可能最终影响肌肉相关疾病的发展。

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Kinesin light chain 1 stabilizes insulin receptor substrate 1 to regulate the IGF-1-AKT signaling pathway during myoblast differentiation

The IGF signaling pathway plays critical role in regulating skeletal myogenesis. We have demonstrated that KIF5B, the heavy chain of kinesin-1 motor, promotes myoblast differentiation through regulating IGF-p38MAPK activation. However, the roles of the kinesin light chain (Klc) in IGF pathway and myoblast differentiation remain elusive. In this study, we found that Klc1 was upregulated during muscle regeneration and downregulated in senescence mouse muscles and dystrophic muscles from mdx (X-linked muscular dystrophic) mice. Gain- and loss-of-function experiments further displayed that Klc1 promotes AKT–mTOR activity and positively regulates myogenic differentiation. We further identified that the expression levels of IRS1, the critical node of IGF-1 signaling, are downregulated in Klc1-depleted myoblasts. Coimmunoprecipitation study revealed that IRS1 interacted with the 88-154 amino acid sequence of Klc1 via its PTB domain. Notably, the reduced Klc1 levels were found in senescence and osteoporosis skeletal muscle samples from both mice and human. Taken together, our findings suggested a crucial role of Klc1 in the regulation of IGF-AKT pathway during myogenesis through stabilizing IRS1, which might ultimately influence the development of muscle-related disorders.

更新日期：2024-02-03

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